The present invention provides a novel composition of matter, novel formulations containing it, novel methods for using it, and a novel process for making it. In particular, the present invention provides substantially uniformly small, pharmaceutically elegant particles of colestipol hydrochloride, pharmaceutical compositions containing them, and methods for using them to treat hypercholesterolemia in humans. These pharmaceutical compositions include tablets (particularly tablets containing greater than 500 mg of drug), palatable or non-gritty oral suspensions or powders (flavored or unflavored), and various drug-containing food products having improved palatability.
Colestipol is a basic anion exchange resin described as a high molecular weight copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane (hydrochloride), with approximately 1 out of 5 amine nitrogens protonated. It is a light yellow resin which is hygroscopic and swells when placed in water or aqueous fluids. See Merck Index (Tenth Edition) #2440, page 2438. Colestipol hydrochloride is commercially available in granule form as COLESTID.RTM. Granules. See Physicians Desk Reference (PDR) 42nd Ed., p. 2119 (1988).
COLESTID.RTM. Granules are marketed as a hyperlipidemia agent for oral use. COLESTID.RTM. Granules are tasteless and odorless, although they may have a pronounced gritty texture when suspended in liquids consumed orally.
Cholesterol is the major, and probably the sole precursor of bile acids. During normal digestion, bile acids are secreted via the bile from the liver and gall bladder into the intestines. Bile acids emulsify the fat and lipid materials present in food, thus facilitating absorption. A major portion of the bile acids secreted is reabsorbed from the intestines and returned via the portal circulation to the liver, thus completing an enterohepatic cycle. Only very small amounts of bile acids are found in normal serum. Physicians' Desk Reference (P.D.R.) 42nd Edition, 1988, page 2115.
Colestipol hydrochloride, e.g., COLESTID.RTM. Granules, is indicated as adjunctive therapy to diet for the reduction of elevated serum cholesterol in patients with primary hypercholesterolemia (elevated low density lipoproteins).
Heretofore the only known form of colestipol hydrochloride was the granulated form, specifically COLESTID.RTM. Granules, which consist of spherical beads of colestipol hydrochloride wherein at least 75% of the particles by weight or volume are greater than 100 microns in diameter and at least 30% of the particles are greater than 80 microns in diameter. These granules must be consumed orally and typically require admixture with a pleasant tasting vehicle at the time of oral consumption. COLESTID.RTM. Granules are greater than 99.5% colestipol hydrochloride by weight. The typical daily dose of COLESTID Granules employed for anti-hyperocholesterolemia varies from 15 to 30 grams per day. Patients taking this medication ordinarily must continue to take anti-cholesterolemic drugs throughout their lives to maintain reduced serum cholesterol levels.
The heretofore known form of colestipol hydrochloride, i.e., COLESTID.RTM. Granules, is not well tolerated by patients since the gritty texture of the product is objectionable, severely compromising the pharmaceutical elegance and patient acceptance. Further, the use of a granule formulation means that drug must be mixed with a liquid vehicle at the time of consumption, an inconvenience for many patients. For example, in order to take this drug, patients must measure the powder, disperse it in a liquid vehicle and drink the entire contents. A pharmaceutically more elegant and convenient dosage form would be a tablet or capsule product. However, ingestion of an unacceptably large number of tablets would be necessary to make the ingestion of colestipol hydrochloride in a tablet dosage form practical. Capsules are physically capable of handling no more than 600 mg of the colestipol hydrochloride. Moreover, the colestipol hydrochloride granules as presently available cannot be tableted in strengths greater than 600 mg without making an unacceptably large-sized tablet.
Heretofore no colestipol hydrochloride has had sufficient pharmaceutical elegance and efficacy to provide patients with a fully convenient and effective drug.